title: Context-dependent signaling defines roles of BMP9 and BMP10 in embryonic and postnatal development.
abstract: Many important signaling pathways rely on multiple ligands. It is unclear if this is a mechanism of safeguard via redundancy or if it serves other functional purposes. In this study, we report unique insight into this question by studying the activin receptor-like kinase 1 (ALK1) pathway. Despite its functional importance in vascular development, the physiological ligand or ligands for ALK1 remain to be determined. Using conventional knockout and specific antibodies against bone morphogenetic protein 9 (BMP9) or BMP10, we showed that BMP9 and BMP10 are the physiological, functionally equivalent ligands of ALK1 in vascular development. Timing of expression dictates the in vivo requisite role of each ligand, and concurrent expression results in redundancy. We generated mice (Bmp10(9/9)) in which the coding sequence of Bmp9 replaces that of Bmp10. Surprisingly, analysis of Bmp10(9/9) mice demonstrated that BMP10 has an exclusive function in cardiac development, which cannot be substituted by BMP9. Our study reveals context-dependent significance in having multiple ligands in a signaling pathway.
authors.affiliation: Department of Molecular Biology, Division of Research, Genentech, Inc, San Francisco, CA 94080, USA.
authors.forename: Hao
authors.initials: H
authors.lastname: Chen
authors.forename: John
authors.initials: J
authors.lastname: Brady Ridgway
authors.forename: Tao
authors.initials: T
authors.lastname: Sai
authors.forename: Joyce
authors.initials: J
authors.lastname: Lai
authors.forename: Søren
authors.initials: S
authors.lastname: Warming
authors.forename: Hanying
authors.initials: H
authors.lastname: Chen
authors.forename: Merone
authors.initials: M
authors.lastname: Roose-Girma
authors.forename: Gu
authors.initials: G
authors.lastname: Zhang
authors.forename: Weinian
authors.initials: W
authors.lastname: Shou
authors.forename: Minhong
authors.initials: M
authors.lastname: Yan
mesh_terms: D030201:Activin Receptors, Type I / Q000378:metabolism*; D030301:Activin Receptors, Type II; D000818:Animals; D057134:Antibodies, Neutralizing; D019485:Bone Morphogenetic Proteins / Q000235:genetics / Q000378:metabolism*; D002319:Cardiovascular System / Q000196:embryology* / Q000254:growth & development* / Q000378:metabolism; D055879:Gene Knock-In Techniques; D055427:Growth Differentiation Factor 2 / Q000235:genetics / Q000378:metabolism*; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D017403:In Situ Hybridization; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence; D012171:Retinal Vessels / Q000254:growth & development / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D057134:Antibodies, Neutralizing; C119152:Bmp10 protein, mouse; D019485:Bone Morphogenetic Proteins; C526108:Gdf2 protein, mouse; D055427:Growth Differentiation Factor 2; D030201:Activin Receptors, Type I; D030301:Activin Receptors, Type II; C498931:Acvrl1 protein, mouse
keywords: angiogenesis; heart development; heart homeostasis; hereditary hemorrhagic telangiectasia